Project Summary The Eck laboratory at the Dana-Farber Cancer Institute studies the structure and regulation of oncogenic protein kinases. We apply our unique structural and mechanistic insights in collaborative drug discovery efforts to develop inhibitors with novel mechanisms of action and with selectivity for mutant kinases. The Research Specialist is an expert in structural biology (primarily X-ray crystallography), protein biochemistry and ligand- binding studies, enzyme kinetics, and computational approaches (including virtual ligand screening) and has extensive experience applying these approaches in studies of protein kinases. She is driving our research program in two major areas of interest: 1) development of mutant-selective inhibitors of epidermal growth factor receptor (EGFR) mutants in lung adenocarcinoma, and 2) the structure, regulation, and mechanism of oncogenic activation of BRAF, which is relevant to many cancers. In our studies of these kinases, we seek to understand at a structural level how the activity of the kinase is normally regulated and how this regulation is subverted by oncogenic mutations. With our collaborators in medicinal chemistry and cellular pharmacology, the Research Specialist is developing inhibitors that are effective against EGFR mutants that are resistant to all current targeted therapies, including exon 20 insertion variants of EGFR and EGFR bearing both the T790M and C797S secondary resistance mutations. In addition, the Research Specialist is working to determine the three-dimensional structure of intact BRAF in an autoinhibited state. This work will show how diverse oncogenic mutations lead to BRAF activation and elucidate the mechanism by which many BRAF-targeted drugs induce paradoxical activation of the wild type kinase. In addition, it can be expected to open new avenues for development of BRAF inhibitors that do not exhibit paradoxical activation, and may therefore be effective in the KIAA1549:BRAF truncation fusion found in pediatric brain cancers.